Survival rates for breast cancer (BC) have steadily improved over the past two decades because of advances in detection and treatment. Observational studies suggest that if breast cancer survivors (BCS) can become sufficiently physically active and control their weight, prognosis may improve even further. While these observational findings are encouraging, the reasons for this protective effect of physical activity (PA) on BC survival will remain speculative until a biologic mechanism(s) that explains this link is established. Equally important is to establish whether or not PA must decrease body fat stores in order to exert a protective effect. In the absence of controlled clinical trials with survival as an endpoint, exercise studies that provide data on biomarkers of cancer progression can substantiate epidemiologic reports and generate new knowledge about the role of exercise and body fat on BC survival. The purpose of the proposed study is to determine the influence of exercise and body fat changes on 3 types of biomarkers (sex and metabolic hormones and adipocytokines) associated with cancer progression in BCS. We have stored serum samples from 3 cohorts of postmenopausal BCS who participated in controlled trials of resistance exercise with primary endpoints of body composition and physical function. We will analyze baseline and post-intervention samples from BCS who participated in either 1 year of resistance training or 1 year of seated stretching exercise (control condition) for 3 types of cancer progression markers. The specific aims of the study are to: 1) determine the influence of resistance exercise on markers of cancer progression and 2) determine whether or not changes in adiposity mediate changes in cancer progression markers. The proposed study is innovative because it will be the first study to combine data from 3 cohorts of BCS participating in similar interventions in order to determine the effects of strength training on 3 types of biomarkers associated with BC progression. The study will also be the first to consider whether or not resistance exercise must reduce fat mass in order for changes in biomarkers to emerge. This R21 application matches the objectives of PA-09-149 calling for new analyses of stored biologic samples to test new hypotheses that will generate knowledge about the relationships among energy balance, cancer prognosis and quality of life. The application also addresses a primary goal of the NCI's Transdisciplinary Research on Energetics and Cancer (TREC) initiative to better understand the mechanisms underlying the association between energy balance and carcinogenesis across the cancer continuum. This study is relevant to public health because BC is the leading cancer in women and BCS have a 67% greater risk of developing a new BC compared to the other women. This research is significant because both clinicians and patients need access to evidence-based, low-cost strategies for lowering risk of recurrence and improving quality of life for BCS. If the aims of the proposed study are achieved, findings from this study will generate new knowledge about the type and design of exercise interventions most likely to improve survival outcomes. PUBLIC HEALTH RELEVANCE: This study is relevant to public health because breast cancer is the leading cancer in women and strategies that improve both survival and quality of life for breast cancer survivors are urgently needed. The proposed study will determine whether exercise reduces biological markers associated with breast cancer recurrence.